Venus Williams falls to the court as she misses a shot against Jie Zheng of China in a tie breaker during the second round of the 2013 U.S. Open tennis tournament, Wednesday, Aug. 28, 2013, in New York. (AP Photo/Darron Cummings)

Andy Murray, of Britain, chases down a return against Michael Llodra, of France, during the first round of the 2013 U.S. Open tennis tournament, Wednesday, Aug. 28, 2013, in New York. Murray defeated Llodra. (AP Photo/Charles Krupa)

Juan Martin del Potro, of Argentina, yells and pumps his fist after beating Guillermo Garcia-Lopez, of Spain, in the first round of the 2013 U.S. Open tennis tournament, Wednesday, Aug. 28, 2013, in New York. (AP Photo/Charles Krupa)

China's Li Na reacts to an instant replay of a shot against Sofia Arvidsson, of Sweden, during the second round of the 2013 U.S. Open tennis tournament, Wednesday, Aug. 28, 2013, in New York. (AP Photo/Kathy Willens)

Mikhail Youzhny, of Russia, reacts during a first round match to Nicolas Mahut, of France, during the first round of the 2013 U.S. Open tennis tournament, Wednesday, Aug. 28, 2013, in New York. (AP Photo/Mike Groll)

Sloane Stephens, of the United States, wipes her brow in her match to Urszula Radwanska, of Poland, during the second round of the 2013 U.S. Open tennis tournament, early Thursday, Aug. 29, 2013, in New York. (AP Photo/Charles Krupa)

Agnieszka Radwanska, of Poland, reacts during her second round match against Maria-Teresa Torro-Flor, of Spain, during the second round of the 2013 U.S. Open tennis tournament, Wednesday, Aug. 28, 2013, in New York. (AP Photo/Kathy Kmonicek)

She stumbled as she stepped into the shot, and the ball bashed into the net. The 33-year-old American stood up slowly and grimaced. After more than three hours, she didn't have one more point left.

Williams lost 6-3, 2-6, 7-6 (5) to 56th-ranked Zheng Jie of China on a wet Wednesday at Flushing Meadows. It is the third year in a row that the two-time champion is out of the U.S. Open after two rounds.

Williams has been slowed the past couple of years by an autoimmune disease that saps energy. Much of this season, she has been hampered by a bad back. And so the questions come about how much longer she'll step onto the court.

"The last few months haven't been easy, coming back from the back injury, one of the more challenging injuries I've dealt with," she said. "I feel like it's definitely affected my game, but I'm working on it. I'm a fighter. Just like today, I didn't play my best, but I tried as hard as I could. Tried not to get down.

"So I'll continue playing matches. For me it would be awesome if I could play another match right away, but unfortunately I have to wait weeks to play. That stops the momentum. Maybe this fall I'm going to maybe enter consecutive tournaments, so even if I do have a bad match I can hopefully play sooner so I can just get some rhythm."

Williams acquitted herself well for stretches, erasing deficits over and over again, until she simply ran out of solutions against Zheng, a former top-15 player and twice a major semifinalist.

In what she took as an encouraging sign, Williams was out there for 3 hours, 2 minutes, tying for the fifth-longest women's match since 1970 at the U.S. Open. The third set alone lasted 1½ hours.

"I was like, 'Wow, this is a marathon,'" Williams said.

She wound up with 44 unforced errors in all, half on forehands, in part because Zheng kept scrambling along the baseline to get to balls and block them back, making Williams hit extra shots.

During her on-court interview, Zheng addressed the partisan crowd that was raucously pulling for Williams in Louis Armstrong Stadium, saying: "First, I want to say, 'Sorry, guys.'"

Rain began falling in the early afternoon, jumbling the schedule, and eight women's singles matches were postponed entirely, including Williams' younger sister Serena against Galina Voskoboeva. More than four hours of delays during the day meant 2012 champion Andy Murray did not play his first point of the tournament until 9:55 p.m., making for the third-latest start to a U.S. Open night session.

Men were playing in the first round, women in the second. Murray's 6-2, 6-4, 6-3 victory over 49th-ranked Michael Llodra of France began in Arthur Ashe Stadium only after 2009 champion Juan Martin del Potro wrapped up a contentious 6-3, 6-7 (5), 6-4, 7-6 (7) victory over 74th-ranked Guillermo Garcia-Lopez of Spain that stretched more than four hours.

Murray, who last month became the first British man in 77 years to win Wimbledon, needed only a little more than 1½ hours to get past Llodra, making just five unforced errors while compiling 34 winners.

A little past midnight, 33-year-old American James Blake's career came to an end with a 6-7 (2), 3-6, 6-4, 7-6 (2), 7-6 (2) loss to 6-foot-10 Ivo Karlovic of Croatia. Blake, once ranked as high as No. 4 and a three-time major quarterfinalist, announced Monday that the U.S. Open would be his last professional tournament.

No. 17 Kevin Anderson of South Africa, No. 20 Andreas Seppi of Italy, No. 21 Mikhail Youzhny of Russia, 2001 U.S. Open champ Lleyton Hewitt and 109th-ranked American wild-card entry Tim Smyczek were among the day's winners. But No. 16 Fabio Fognini, No. 24 Benoit Paire and No. 29 Jurgen Melzer lost, meaning 10 of the 32 seeded men bowed out in the first round.

The last match of the long day began in Ashe shortly before midnight, and it was over before 1 a.m., because 15th-seeded American Sloane Stephens needed only 58 minutes to beat 38th-ranked Urszula Radwanska of Poland 6-1, 6-1.

"Before the match, I was like, 'Man, normally I would be sleeping at this time," said Stephens, who will play No. 23 Jamie Hampton in an all-American matchup in the third round.

Radwanska's older sister, 2012 Wimbledon runner-up Agnieszka, was among the women who won earlier, along with 2011 French Open champion Li Na, and No. 30 Laura Robson of Britain. Robson beat Li last year in New York, and now they'll have a rematch.

Venus Williams and Zheng played all of two points before being interrupted by showers. When they resumed two hours later, Williams kept making mistakes.

"I couldn't pray a ball in," she said.

But in the second set, Williams looked more like someone who won the U.S. Open in 2000 and 2001, and five Wimbledon titles.

Zheng led 4-1 in the tiebreaker, before Williams made one last stand. But at 5-all, Williams missed that volley.

"I should have made the shot," Williams said. "I was just rushing."

Zheng then converted the match point.

As Williams pointed out more than once during her news conference, there's still doubles to play with her sister.

The older Williams hasn't been ranked in the top 10 in 2½ years. The last time she made it beyond the third round at a major tournament was a fourth-round appearance at Wimbledon in 2011.

At the 2011 U.S. Open, Williams withdrew before her second-round match, announcing she had Sjogren's syndrome, an illness that causes joint pain and fatigue.

Two of her previous four trips to major tournaments ended in the first round, including at the French Open in May. Because of her back, Williams sat out Wimbledon for the only time in her career in June.